Epithelial-Mesenchymal Transition Markers in the Differential Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors

Objectives: To elucidate the role of epithelial-mesenchymal transition markers in gastroenteropancreatic neuroendocrine tumors (GEE NETs) and the potential usefulness in their clinical management. Methods: One hundred ten GEE NET paraffin-embedded samples were immunohistochemically analyzed for E-cadherin, N-cadherin, beta-catenin, vimentin, Snail1, Snail2, Twist, and Foxc2 protein expression. Results: The 5-year survival rate was reduced for those patients showing high Snail1 protein levels, a cytoplasmic E-cadherin pattern, reduced N-cadherin expression, and loss of E-cadherin/beta-catenin adhesion complex integrity at the cell membrane. Interestingly, high beta-catenin expression was useful in identifying a grade 1 NET subgroup with a favorable clinical course. Importantly, it also helped to discriminate small-cell vs large-cell grade 3 neuroendocrine carcinomas. Conclusions: beta-Catenin and N-cadherin immunohistochemical detection might be a useful tool in the differential diagnosis of small-cell vs large-cell G3 neuroendocrine carcinomas. High Snail1 and Foxc2 expression is associated with the invasion and metastatic spread of GEE NETs.